Bisphosphonate-Associated Osteonecrosis of the Jaw (BP-ONJ) and Associated Clinical Findings Within a Large Integrated Healthcare Delivery System in Northern California

Abstract

BP-ONJ is an emerging problem seen in patients receiving bisphosphonate (BP) therapy, particularly among individuals receiving intravenous aminobisphosphonates (pamidronate disodium or zoledronic acid) for treatment of multiple myeloma and metastatic cancers affecting bone. Sporadic cases of ONJ have also been reported among individuals receiving oral aminobisphosphonates for osteoporosis. We utilized health plan databases and maxillofacial surgery clinic records to identify all patients with a diagnosis of BP-ONJ between 2004-2006 within Kaiser Permanente Northern California, a large integrated community-based health plan that provides comprehensive medical care, including oral and maxillofacial surgery care, to over 3 million members. With detailed demographic, clinical, and pharmacologic data, we conducted a systematic review of identified BP-ONJ cases to determine the frequency of associated clinical findings and pharmacologic exposures. A retrospective cohort study was completed by reviewing health plan databases and medical charts. Information on demographic data, clinical comorbidities (cancer, osteoporosis, Paget’s disease, diabetes status) and pharmacologic exposures (oral and IV BP dose and duration, glucocorticoid and thalidomide use) were ascertained. BP-ONJ was defined by the presence of exposed bone for more than 8 weeks duration in patients with current or prior treatment with IV or oral forms of aminobisphosphonates. Patients with osteoradionecrosis (or a history of head and neck irradiation) and osteomyelitis of other etiologies were excluded. Standard descriptive statistics were used to describe the characteristics of the cohort and chi-square test was used for comparison between disease and treatment subgroups. A total of 47 patients (61.7% White, 12.8% Asian, 10.6% Black, 6.4% Hispanic and 6.4% other/unknown) with confirmed BP-ONJ were identified from maxillofacial surgery clinic files and coded electronic diagnoses. The average age was 66.5 ± 10.6 years and 59.6% were female. There were 17 (36.2%) individuals with multiple myeloma, 13 (27.7%) with metastatic breast cancer, 8 (17.0%) with metastatic prostate cancer, 2 (4.3%) with other malignancies metastatic to bone, 1 (2.1%) with Paget’s disease, and 6 (12.8%) with osteoporosis. Seven (14.9%) patients developed ONJ in the setting of exclusive oral BP exposure, 6 (12.8%) received both oral and IV BP, and the remaining 34 (72.3%) received exclusive IV BP. Among patients receiving IV BP, the median number of doses was 20 (interquartile range 11-37). Among patients receiving only oral BP, duration of treatment ranged from 2-7 years using KPNC pharmacy records. Almost one third (29.8%) of ONJ cases had diabetes mellitus, with a similar proportion of diabetics in the IV BP and exclusive oral BP groups (p=0.9). There were 12 (25.5%) patients with current or prior thalidomide use, most of whom (75.0%) had multiple myeloma. Most patients (83.0%) had current or prior glucocorticoid therapy, particularly patients with multiple myeloma (94.1%) compared to those without (76.7%), although the difference was not statistically significant (p=0.13). Finally, 13 (27.7%) received warfarin therapy, of whom 7 (53.9%) had multiple myeloma treated with thalidomide. Of these 13 individuals, 6 (12.7%) received warfarin for prior venous thromboembolism while the remaining 7 (14.9%) received warfarin as prophylactic anticoagulant therapy. Within a large integrated health care delivery system, we identified at least 47 patients of BP-ONJ from clinic records and electronic databases. Most cases occurred in the setting of IV BP exposure, although among the 47 cases, 7 (15%) developed ONJ in the setting of exclusive oral BP treatment. The high prevalence of diabetes and glucocorticoid therapy, as well as the potential role of other pharmacologic agents (e.g. thalidomide) and hypercoagulable states warrant further investigation.